The present invention provides compounds that are selective allosteric modulators of the M4 subtype of muscarinic receptor. The M4 muscarinic receptor is believed to play a role in modulating synaptic function in key areas of the brain involved in regulating mood, cravings, attention and cognition. As a result, it provides a novel therapeutic target for the treatment of psychosis; attention disorders, such as attention deficit hyperactivity disorder (ADHD); cognitive disorders, including memory loss; and drug addiction. The M2 and M4 subtypes of muscarinic receptor are also involved in muscarinic agonist-induced analgesic effects, but it is believed that side effects of such treatment are associated primarily with M2 receptor activation. Thus, compounds that selectively modulate M4 receptors would provide a novel treatment strategy for neuropathic pain, without unwanted side effects.
Unlike compounds that act at the neurotransmitter binding site (orthosteric site), allosteric modulators act at a distinct site on the receptor. The use of allosteric modulators provides several advantages in the treatment of disease. Christopoulos, Nature Reviews (2002) 1: 198-210. For instance, under saturating conditions (high concentrations of allosteric potentiator) one would not expect excessive stimulation of the M4 muscarinic receptor, since it is dependent on the endogenous neurotransmitter for activation. Second, allosteric agonists exert their physiological effects only in the presence of endogenous agonist. As a result, allosteric potentiators are less likely to produce the condition of receptor desensitization or down-regulation that are associated with excessive cholinergic stimulation. Finally, allosteric modulators are likely to show greater receptor selectivity, especially as the orthosteric binding site is well conserved between muscarinic receptor subtypes.
At present, no selective allosteric modulators of the M4 subtype of muscarinic receptor have been reported. The development of selective M4 allosteric potentiators will therefore greatly enhance the ability to treat disorders such as psychosis and pain, without unwanted side effects. Thus, the present invention provides a class of allosteric modulators of M4 muscarinic receptors, compositions comprising these compounds, and methods of using the compounds.